When describing his latest effort to make breakthroughs for children with cancer, Adam Resnick, PhD, places it in the context of history. In their origins, science and medicine were once entirely separate disciplines, he notes. Science, an erudite pursuit to unlock the universal truths of the natural world, rarely concerned itself with concerns of human flesh. Medicine, meanwhile, was more personal — a direct relationship between a patient and a healing hand.

“These different approaches are coming together in new and amazing ways,” Dr. Resnick said during an event he hosted in September with colleagues from the Center for Data-Driven Discovery in Biomedicine (D3b) at Children’s Hospital of Philadelphia.

Henrietta Lacks and How Patients Now Help Medicine and Science Converge

The guest of honor at the September event was David Lacks, a man whose family’s recent history helps to illustrate just how recent and how essential — for patients and for scientific knowledge — the modern convergence of medicine and science turns out to be.

David’s grandmother, Henrietta Lacks, a poor African-American woman who grew up on a tobacco farm and raised her family in Baltimore, died of cervical cancer in the early 1950s. But her cancer cells lived on; a tissue sample, taken by her doctor without her knowledge and handed off to a scientist colleague, had become the first human cells to grow and reproduce perpetually in the lab. The cells, called HeLa, helped power breakthroughs including vaccines and cancer therapies, and they remain an essential tool in biomedical science.

In part because the cultures of science and medicine decades ago regarded scientific pursuits using cells as discrete and disconnected from the human patient in the hospital (and exacerbated by other racial and sociocultural dynamics), the Lacks family did not learn of their late matriarch’s contributions to science until decades later. They struggled to gain any insight into how the cells were being used and what that meant. After halting progress and the 2010 publication of a book about Henrietta, the Lacks family now has an active role in deciding how genomic data from HeLa cells can be used in research. Now that they are engaged as partners with scientists and have the opportunity to make choices to protect their genetic privacy on their own terms, they want to use Henrietta’s legacy to drive scientific progress.

“It’s important,” David Lacks said during his visit to CHOP. “We all get sick, we’re all going to get old, we all might suffer from something. Why stand in the way? Why not try to be a catalyst to help and change, as opposed to blocking it?”

This new level of family engagement is emblematic of the moment in history when it occurred. This decade marks an inflection point in history when the medical realm — the family of a single patient —can link directly to the process of scientific discovery by being an active partner in it. Dr. Resnick and his team at CHOP’s D3b center believe that it is families and patients who can actually lead this charge. When facing a serious disease such as childhood cancer, and especially highly lethal cancers such as brain tumors, patients and their families commit deeply to hopes for both medicine and science — medicine to treat the patient’s own disease successfully, and science to spare future families a similar struggle. Empowering patients and families to engage and achieve maximum success with the scientific aim is where the heart of his team’s newest initiative comes to life.

The astounding glut of data created in the course of trying to solve serious diseases may itself be one of the most dominant challenges in the 21st century. Analyzing patients’ biological samples with newer sequencing tools results in huge amounts of data about genes and genomes, RNAs, and proteins. Making sense of that sequencing data requires a huge amount of computational power.

At the same time, organizational structures divide how clinical and research data can be shared and used to gain collaborative insights. Many pediatric diseases, including childhood cancers, are so rare that no one hospital or healthcare network can amass enough samples or data to gain meaningful insights into the molecular drivers of these diseases. These challenges drove the creation of multi-institutional research and clinical trial consortia such as the Children’s Brain Tumor Tissue Consortium (CBTTC), and the Pacific Pediatric Neuro-Oncology Consortium (PNOC), in both of which Dr. Resnick serves as the scientific chair. The D3b center at CHOP was established in December 2015 to build on the work of these consortia and break down silos that keep data separate and further empower the development of a data-driven ecosystem on behalf of CHOP’s diverse patient population.

One of this group’s first major initiatives is the launch of its open-access pediatric genomic data cloud, CAVATICA, announced in October 2016 as a private commitment in conjunction with the national Cancer Moonshot. CAVATICA gives clinicians and scientists secure access to big data about pediatric diseases that is empowered for secure, collaborative analysis through scalable cloud computing — meaning that the users of the service do not need to bring their own high-powered computers in order to perform complex analyses of vast quantities of data. Contributions from CBTTC and PNOC will collectively represent data from more than 20 pediatric hospitals. Researchers worldwide will be able to access this information and work together to fully empower and share novel ideas and approaches for new biological targets for precise, less toxic clinical treatments on behalf of children. CAVATICA is a joint venture of the CBTTC and PNOC created in partnership with Seven Bridges Genomics, a National Institutes of Health trusted data partner.

Patients and families who choose to partner in research and share their data with the CBTTC, PNOC, or other participating consortia and organizations, will contribute to CAVATICA, and individual patients will also be able to contribute data to CAVATICA directly. Patients will able to decide whether to remain anonymous or associate the data with their identity, and they can know that their contribution is likely to be more powerful by joining together with other patients at a scale large enough to drive powerful discoveries.

“Data can be immortalized forever, and that’s a legacy that patients and families leave behind when they choose to contribute to research in the face of serious and sometimes lethal diseases,” Dr. Resnick said. “It is our responsibility as partners in research to honor that legacy to support discovery of new treatments and new cures for childhood diseases.”

Benjamin Yerys, PhD, is a psychologist trying to unravel a problem that, up until a few years ago, did not officially exist. Prior to the publication of the most recent fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the official party line among mental health professionals was that a child who had autism spectrum disorder (ASD) could not also have attention-deficit/hyperactivity disorder (ADHD).

“They would just say, ‘Well, the autism spectrum is just really wide. That’s not really ADHD. That’s autism,’” Dr. Yerys recalled of the presiding sentiment at that time.

Now, children can and do have diagnoses of both ADHD and ASD. They account for about 30 percent of children with an ASD diagnosis, and there is an added problem in these tangled cases: “We’re doing a much poorer job treating ADHD in kids with autism compared to other kids with just ADHD,” Dr. Yerys said. “I want to understand why that’s the case.”

Research on treatments of attention symptoms, whether with stimulants including methylphenidate (Ritalin®) or non-stimulant medications, shows that these treatments have relatively high response rates among children with ADHD in the general population and relatively low incidence of severe side effects. Among children with ASD, response rates to ADHD treatments are much lower, while side effects occur much more often.

To get at the question of why that is and what can be done to better help children with both ASD and attention problems, Dr. Yerys and colleagues at CAR pursued research to see if ADHD was even being measured correctly in children on the autism spectrum. Inaccurate measurements — such as misdiagnoses of ADHD in some children with ASD — could explain why the treatments work poorly in so many of these children. They are simply the wrong treatments.

To ask these questions, Dr. Yerys worked with a colleague who created one of the most widely used tools for diagnosing ADHD in the general population. Thomas Power, PhD, director of CHOP’s Center for Management of ADHD, co-developed the ADHD Rating Scale Fourth Edition (ADHD-RS-IV) in the 1990s. This is a well validated tool that asks parents and teachers to provide numerical ratings in reply to 18 items about a child’s behavior: nine items on inattention and nine on hyperactivity and impulsivity. Testing the rating scale across a wider population of children with ASD, the researchers found that some questions about inattention and one about hyperactivity were poorly related to the other questions of inattention and hyperactivity/impulsivity, respectively. While this finding does not negate the usefulness of the tool for identifying ADHD symptoms in some children with ASD, it shows that it is flawed when used in children with ASD and potentially too sensitive to behavioral differences in this group that do not actually reflect ADHD. The findings were published in the Journal of Autism and Developmental Disorders.

“We’ve learned from this that maybe we need to be a little more careful in making an ADHD diagnosis,” Dr. Yerys said. “Even specialists need to step back and do a little bit more careful interviewing to make sure that when a parent says, ‘Yes, my child is easily distracted,’ is that really about being just distracted?”

Until more effective diagnostic tools are developed for this population, clinicians should consider the circumstances of a child’s reported behavior to distinguish the possible contribution of autism-related differences, he noted. His hypothesis is that social differences related to autism might be misinterpreted as signs of ADHD if the social component of behaviors are not taken into account. Does the child fail to stay focused on a topic of conversation with others because he is easily distracted, or is he simply not attuned to the social conventions of taking turns speaking and engaging in another person’s interests?

Dr. Yerys and colleagues, including Dr. Power and CAR director Robert Schultz, PhD, hope to pursue further research to confirm this hypothesis. They also hope to interview parents about what behaviors are typical in children with both ADHD and ASD to establish better questions to differentiate this subgroup from children with only ASD using an improved diagnostic test.

“I’m excited to be involved in this study, and in efforts to refine our screening tools for ADHD among various populations of children,” said Dr. Power, who is also associate chief of academic affairs in the department of Child and Adolescent Psychiatry and Behavioral Sciences at CHOP and a professor of School Psychology in Pediatrics and Psychiatry at the Perelman School of Medicine at Penn. “This study makes a unique contribution because few researchers have previously investigated the use of rating scales for ADHD among children with ASD. Our research raises questions not only about this assessment tool, but all such measures that rely on parent and teacher ratings to assess ADHD in children with ASD.”

In addition to working to improve diagnostic tools, Dr. Yerys is pursuing a separate line of research also aiming to help this population. Using brain imaging tools, he is trying to learn if attention problems in children with ASD have the same underlying biological causes as they do in children with only ADHD. A different underlying biological cause could help explain why ADHD medications seem not to work as well in the ASD population. At the same time, any new insights about the biological causes of attention problems in ASD could point to what different treatments might work better in this group.

“The biggest problem we have in all of psychiatry, not just autism, is that when a treatment doesn’t work, we don’t know why,” Dr. Yerys said. “We hope to know which treatment is the right treatment for someone. That’s the whole idea behind personalized medicine, and that’s really where this line of research is headed.”

Dr. Ohene-Frempong’s son was the first baby diagnosed with the disease by Howard Pearson, MD, in the pioneering newborn screening program at Yale in 1972. As a young fellow in pediatric Hematology-Oncology at CHOP, Dr. Ohene-Frempong worked with Frances Gill, MD, in a research newborn screening project at HUP in 1978. As Director of the Sickle Cell Program at CHOP, Dr. Ohene-Frempong launched a city-wide pilot program for the inherited blood disorder in Philadelphia in collaboration with the Pennsylvania Department of Health. Based on his research, Pennsylvania’s health department began shortly thereafter to conduct newborn screening for sickle cell disease at the state level.

“I realized that we were testing babies at birth and saving lives,” Dr. Ohene-Frempong said. “If we only wait for those who come to the hospital sick to care of them, we would only be treating the tip of the iceberg because many more would have died and never reached us. So while I was in training, one of my goals was to one day be in a position to take what I learned and start a program like that in Ghana, where sickle cell disease is so common.”

Dr. Ohene-Frempong went on to conduct a 15-year research program funded by the National Institutes of Health that established the feasibility of conducting similar screening programs in Kumasi, the second largest city in Ghana. The research project started in December 1992 with a clinic for 10 patients at the Komfo Anokye Teaching Hospital. It now serves more than 10,000 patients with sickle cell disease and has outgrown its capacity.

All of those efforts laid the groundwork for the construction of a new sickle cell center of excellence in Kumasi for treatment and research. The Sickle Cell Foundation of Ghana, which Dr. Ohene-Frempong founded, received $4.5 million from the Ghana National Petroleum Corporation in March to begin the project, which will modernize the care of people with sickle cell disease in Ghana.

“Our need for a place to hold clinic and provide some of the other important tests we do for sickle cell disease has become very great,” Dr. Ohene-Frempong said. “A center like this will help us develop better treatment models for all the other hospitals and clinics in the country to learn from. It is a big responsibility, and I am happy we have the opportunity to embark upon it.”

Early Diagnosis Crucial

Eighty percent of children who have sickle cell disease are born in Sub-Saharan Africa, Dr. Ohene-Frempong said. Yet, approximately 5 percent of the world’s population carries trait genes for hemoglobin disorders including sickle cell disease, according to the World Health Organization. Sickle cell disease results when red blood cells make mostly hemoglobin S, which can turn the cells into hard and sticky pointed shapes like crescents or sickles that can damage blood vessels, instead of the normal hemoglobin A, which allows the cells to be smooth, round, and soft so they can move easily through blood vessels.

Fifty to 90 percent of children with sickle cell disease in Africa die before age 5, often after a short illness with a fever caused by a bacterial infection. In many cases, these children are undiagnosed because they are not yet showing the signs commonly associated with sickle cell disease, such as chronic anemia, fatigue, and periodic episodes of pain. Physicians often jump to the wrong conclusion that malaria is to blame for the child’s death. Early diagnosis through newborn screening and prompt treatment with penicillin prophylaxis can help prevent these life-threatening infections, giving children with sickle cell disease a better chance of survival, Dr. Ohene-Frempong said.

“In the U.S., we have done research to show that if we diagnose sickle cell disease at birth, or soon after birth, and give young children preventative treatment from about 2, 3 months of age, we are able to reduce quite remarkably the leading cause of death related to sickle cell disease, which is infection from bacteria,” Dr. Ohene-Frempong said. “So it is important to find these babies.”

Dr. Ohene-Frempong has been an advocate for the establishment of a national newborn screening program for sickle cell disease in Ghana, but its expansion to districts beyond Kumasi has been slow due to lack of government funding. Currently, only about 35,000 babies are screened each year in Ghana, but ideally that number should be closer to 800,000, Dr. Ohene-Frempong said. He anticipates that building the new sickle cell center of excellence will help to build national awareness of how deadly the disease can be at a young age and promote newborn screening efforts and early disease management.

Increasing Awareness of Sickle Cell Disease Inheritance

In addition to providing much needed medical services for people with sickle cell disease and space for researchers looking to discover better treatments, the center will be a training center where physicians, nurses, social workers and others from hospitals in Ghana and beyond can learn about modern treatment models and genetic counseling approaches. Dr. Ohene-Frempong anticipates that CHOP will have strong participation in the center by sending clinicians to share their expertise.

Lack of knowledge about how sickle cell disease is inherited is pervasive in Africa, Dr. Ohene-Frempong said, even though it is so common. In an article published in the Journal of Community Genetics, Dr. Ohene-Frempong and other sickle cell experts described how they used qualitative research methods to understand community issues and potential challenges to the development and implementation of a sickle cell counselor training and certification program that the Sickle Cell Foundation of Ghana launched in 2015. The goal of the program is to train physicians, nurses, health educators, and eventually lay counselors, such as teachers, to provide their communities with correct information so that people can understand the implications of sickle cell disease, encourage them to know their sickle cell disease status, and make informed healthcare and reproductive planning decisions.

Sickle cell disease results from the inheritance of the sickle cell gene from both parents, or the sickle gene from one parent and another abnormal hemoglobin gene that contributes to the pathological effect of the sickle gene. Asymptomatic sickle cell trait, which Dr. Ohene-Frempong carries, results from the inheritance of the sickle gene from one parent and the normal version from the other. Most people who are at risk of having a child with sickle cell disease don’t know that they are carriers because they are healthy, and Ghana does not require people to be tested for sickle cell disease or sickle cell trait before marriage.

Special Recognition for Lifetime Achievements

Dr. Ohene-Frempong realized that he is a carrier of sickle cell trait when he underwent medical testing to compete in track and field for Ghana in the 1968 Olympics in Mexico City, which he declined to participate in because the games would interfere with his studies at Yale. He had received a special scholarship to attend college in the U.S., and his goal was to become a doctor, which gave him the opportunity to give back to his country in myriad ways.

While he didn’t receive an Olympic medal, Dr. Ohene-Frempong received one of Ghana’s most prestigious honors and is considered a national hero. In recognition of his leadership, inspiration, and profound commitment to improving sickle cell disease diagnosis and treatments in the U.S. and abroad for more than three decades, Dr. Ohene-Frempong received a Millennium Excellence Award at a ceremony in December 2015.

“I was completely surprised, and it was a pleasant recognition not only of my work in sickle cell disease, but for the work my colleagues in Ghana have been able to accomplish,” Dr. Ohene-Frempong said. “I am only a catalyst for much of that activity, since I’m only a visitor from time to time, but there are many others who continue to work hard.”

Innovative Approaches, Future Research

In July, Dr. Ohene-Frempong, who also is an attending hematologist at CHOP and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, returned to Ghana for the 6th International African Symposium on Sickle Cell Disease organized by the Comprehensive Sickle Cell Center at CHOP. Healthcare workers, public health officials, laboratory technologists, community-based organizations, and support groups for patients and families convened to discuss genetic counseling strategies and psychosocial interventions in Africa.

As the symposium and news of the center of excellence builds momentum for sickle cell disease strategies in Africa, Dr. Ohene-Frempong is equally enthusiastic about research efforts underway at CHOP, including gene therapy. While sickle cell disease is complex, its cause at the genetic level is a relatively simple gene mutation. It’s like misspelling a word, he explained, and the same letter is misspelled for everyone in the world who has sickle cell disease.

“The ultimate gene therapy will fix that error by changing the one letter,” Dr. Ohene-Frempong said. “The current gene therapy trials are introducing the normal version of the gene into the abnormal version. We think this will create cells that have the corrected gene in them.”

One of the researchers working on new gene therapy approaches is Stefano Rivella, PhD, who is the first person to hold the Kwame Ohene-Frempong Endowed Chair in Pediatric Hematology, which was established in 2015 in honor of Dr. Ohene-Frempong’s son.

The wriggling supine baby reached up toward the jungle-themed play gym that arced above her and grabbed a dangling elephant by the trunk. As she squeezed it, the elephant squeaked. She smiled, released, and grabbed the elephant again, this time joining in with a happy squeak of her own.

“It was beautiful to watch her discover the relationship between action and noise and elicit it, and that was the kind of thing we want to test,” said Michelle Johnson, PhD, an assistant professor of physical medicine and rehabilitation at the Perelman School of Medicine at the University of Pennsylvania and in Bioengineering at the School of Engineering and Applied Sciences (SEAS). “If, in comparison to an age-matched infant who we suspect might experience delays in development, does that child even discover the elephant toy?”

Such comparisons between healthy babies playing in the gym and babies with suspected motor delays are all part of the design in this play environment, a high-tech setup built in Dr. Johnson’s Rehabilitation Robotics Lab. Dr. Johnson is collaborating with Laura Prosser, PT, PhD, a physical therapist and rehabilitation scientist at Children’s Hospital of Philadelphia and assistant professor of Pediatrics at the Perelman School of Medicine at Penn, in a research effort to help identify babies at risk for motor delays much earlier than is currently possible.

Babies who are born extremely premature or with conditions that affect their brain development are at elevated risk of motor, cognitive, and other types of delays as they grow. Some babies benefit from early intervention services to help make up for delays.

“The problem is being able to correctly predict which babies will have delays and which ones won’t,” Dr. Prosser said.

Typically, when evaluating an infant who is at risk for motor delays, clinicians like Dr. Prosser observe babies moving and monitor their progress toward major milestones such as sitting up, crawling, and walking. They use standardized tests to determine a clinical score that compares their development to the typical development of infants their age. But no quantitative tools exist to compare detailed information about how babies learn to move and control their movements, such as exactly how babies hold toys when starting to reach, or how small movements of their trunk support more mature kicking patterns. This type of information is needed to identify babies with likely motor delays months before they miss the obvious milestones, when the impact of early rehabilitation might be greater.

That is what led Dr. Prosser and Dr. Johnson to stuff a squeaky elephant toy (and a monkey and a lion) with grasp sensors and inertial motion sensors consisting of a gyroscope and accelerometer.

“We conceived together this concept of a smart gym environment with systems we could build in the lab for earlier diagnosis of infants,” said Dr. Johnson, whose past work has involved development of robotic and other technological rehabilitation tools for adults recovering from stroke and adults with cerebral palsy. “We want to determine whether our engineering rehab tools could support the process of detecting motor deficits in infants before any of the clinical tools that are out there can do that, and we are especially excited because if we are successful, then we could get infants who need rehab the help they need earlier.”

During the first year of the two-year project, they built several prototype versions of the gym, which entailed design challenges distinct from the robotic building efforts in Dr. Johnson’s previous efforts. Ordinarily, she noted, people would develop a more constrained experimental setup to test a limited type of skill or motion so there would be few variables and simpler measurements. Instead, the gym allows babies to play naturally and collects vast amounts and types of data from built-in sensors and video monitoring.

As a result, the data analysis of this gym will be complex, integrating multiple types of data from multiple toys, cameras, and the mat itself, including movements and compression of the toys, the baby’s rolling or crawling motion, and other natural interactions between the baby and the gym.

“Our vision was, we wanted something that ultimately could be placed in a home, in a doctor’s office, or in a day care, a product that would in an unobtrusive way capture this information while the babies play naturally,” Dr. Johnson said. “That means we need to use more modern data analysis tools to try to put our arms around the complicated data we get about babies’ movements.”

Now in its second year, the project has moved to a pilot study of the potential to use the gym and its data to detect meaningful differences in motor skills between 12 typically developing babies and 12 babies who are at risk for motor delays.

“What we hope to learn from this first round of clinical testing is, can these types of sensors and this type of instrumentation identify that babies who are at risk move differently from babies who are typically developing?” Dr. Prosser said. “If that’s the case, then the next steps will be refining the algorithms to quantify those measured differences, and display the metrics in a user friendly interface so parents can see immediately how their baby is moving.”

If the measurement aspect of the study is successful, the researchers hope to receive funding to expand their testing to improve the measurements. They also want to expand future testing into community settings such as homes and daycares, and to test enough babies to define and differentiate both typical and impaired abilities by age and diagnosis, and to consider expanding beyond their initial measurements of motor development to also measure cognitive development.

A long-term vision includes refining the gym so that it is not just a measurement tool, but also a rehabilitation tool that can be individualized to each baby’s specific needs — placing a toy that lights up above her weaker right arm to encourage her to reach in that direction, or placing that squeaky elephant near her left hand to help her to build her grip strength, for example.

Making the toy natural, unobtrusive, and easy for babies to use, but also inexpensive, further appealed to Dr. Johnson because of her lab’s focus on developing affordable rehabilitation tools for developing countries. Many developing countries lack the clinical tools and expertise to diagnose motor delays in young babies, but a toy that could both detect problems and help fix them through natural play might offer benefits to more people in more places.

The researchers are still actively recruiting babies for the pilot tests of the gym, including both typically developing and at-risk babies age 3 to 11 months. Clinicians, parents, childcare professionals, or others who are interested in learning more can contact Dr. Prosser or Dr. Johnson for details.

A special space is open on the walls of Adeline Vanderver, MD’s, new office for a framed collage of “Commander” Massimo “Mo” Damiani, a toddler wearing an orange jumpsuit who looks ready to join a NASA astronaut team. Dr. Vanderver, a child neurologist and geneticist, helped to pinpoint his rare subtype of leukodystrophy, a group of inherited degenerative diseases that affect the white matter in the brain and spinal cord. Gratified to have a diagnosis after three years of searching, Mo’s father sent Dr. Vanderver the portrait with the message, “Mission Accomplished.”

In 2009, 1-year-old Mo was enrolled in a research project that Dr. Vanderver was running out of her lab at the Children’s National Medical Center in Washington, D.C., to perform whole genome sequencing for unclassified white matter disorders. At the time, almost 50 percent of patients suspected of having a form of leukodystrophy didn’t attain a specific molecular diagnosis.

“We knew they had a problem with the white matter of their brain, but we didn’t know what caused it, what their prognosis might be, and what their lifespan might look like,” Dr. Vanderver said. “And so initially I became interested in helping provide an end to their diagnostic odyssey and provide better access to diagnostic services for those patients.”

And that is exactly what Dr. Vanderver did when she used next-generation sequencing applications to discover that mutations in the DARS gene were the reason why Mo had lost basic skills such as crawling, sitting, and talking shortly after his first birthday. Leukodystrophies are caused by genetic defects that affect growth or formation of the myelin sheath, which is soft, white, fatty material that acts as insulation surrounding nerve fibers. Without this protective coating intact, brain signals don’t travel effectively, and children with leukodystrophies face a range of potentially devastating neurological problems that in some cases can lead to a rapid decline in movement, speech, vision, and hearing.

Currently, leukodystrophies number about 30 disorders, and scientists estimate they occur in one in 7,000 births. Yet, leukodystrophies remain widely under-recognized outside and within the pediatric medicine community, Dr. Vanderver said. She works closely with the Global Leukodystrophy Initiative, an advocacy group that includes parents, clinicians, and researchers, to raise disease awareness and ensure that patients receive appropriate social and medical support.

Usually, when a child is diagnosed with a type of leukodystrophy, the family has never heard of the disorder before, which can seem intimidating and frightening, Dr. Vanderver said. Medical practitioners can be equally uninformed and send parents the incorrect message that there is nothing that can be done to help their child.

“Most of these disorders are not curable at this point, but that doesn’t mean they’re untreatable,” Dr. Vanderver said. “A large amount of symptomatic management can be done to improve their health outcomes and quality of life.”

In her new role, Dr. Vanderver and the multidisciplinary staff at the Leukodystrophy Center of Excellence will be creating standards of care for patients to optimize their disease management. In parallel with this strong clinical program, she will spearhead pre-clinical and clinical research projects to discover molecular therapeutics that target the genetics of leukodystrophy subtypes.

Already, Dr. Vanderver is leading two clinical studies that intend to repurpose medications — one that is currently used to treat human immunodeficiency virus and another that targets interferon — for patients with Aicardi-Goutieres syndrome. Another clinical trial that she has underway is assessing the efficacy and utility of whole genome sequencing as a first-line diagnostic test for leukodystrophies.

“We’re hopeful that we’ll be able to take that list of 30 disorders and check them off one by one to get them diagnosed earlier and eventually to deliver therapeutics,” Dr. Vanderver said. “Because that would really be mission accomplished.”

She’ll need a top flight crew to reach those new frontiers, which is partly why Dr. Vanderver is excited to be a new CHOP investigator. She is eager to meet with other clinicians and researchers interested in exploring leukodystrophies or overlapping conditions.

“CHOP has an overall infrastructure that is very supportive, and there are wonderful collaborators to partner with,” said Dr. Vanderver, who also holds the Kamens Endowed Chair in Neurological Disorders and Translational NeuroTherapeutics at CHOP.

The Leukodystrophy Center of Excellence launched in May 2015 to support newborn screening for degenerative inherited white matter diseases, provide integrated multidisciplinary care, and advance research. Amy Waldman, MD, a CHOP pediatric neurologist, is medical director of the Center, which sees patients with leukodystrophies from all over the country and the world.

The brain is an energy hog, consuming more energy than any other single organ despite its small size relative to the rest of the body. Scientists are increasingly considering the possibility that subtle defects in energy consumption could help explain some neurological and neuropsychiatric diseases and conditions — and ultimately lead toward identifying better treatments.

“Schizophrenia is a very heterogeneous problem, so you can’t really find just one cause,” said Stewart Anderson, MD, a research psychiatrist at Children’s Hospital of Philadelphia. “Instead, you can try to find common denominators, and one of the common denominators over the years has been that some people with schizophrenia have metabolic problems that you can detect in their blood.”

Dr. Anderson is leading a new study, funded by the National Institute of Mental Health, focused on an underlying cause of some metabolic problems that could relate to the mechanism of disease in schizophrenia, a severe, chronic, often disabling mental health condition that typically emerges in adolescence or young adulthood and involves distorted and confused thoughts and sometimes paranoia and hallucinations.

The idea is that one of the multiple underlying causes of schizophrenia could involve disruptions — even subtle ones — in the power plants of the body’s cells, the mitochondria, and that these disruptions in brain cells could affect brain functions. These bean-shaped organelles have their own DNA that codes for essential genes for making energy, distinct from the DNA in the cell’s nucleus, and their activities are also influenced by hundreds of genes in nuclear DNA. A key leader and founder of the field of mitochondrial medicine, Douglas Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP, is a co-investigator with Dr. Anderson on the project.

To find out whether and how genes that control mitochondrial function could influence the development of schizophrenia, the researchers are delving deeper into the genetics of a schizophrenia-associated genetic condition, Chromosome 22q11.2 deletion (22q11.2DS). Six of the 41 genes that are on the segment of DNA lost in this deletion of a segment of nuclear DNA are genes that code for proteins that localize to the cell’s mitochondria. At the same time, about 25 percent of people with this deletion develop schizophrenia, a rate 25 times higher than the one percent incidence in the general population.

“Why are 75 percent of them not developing schizophrenia?” said Dr. Anderson, who is also associate professor of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania. “Our hypothesis is that the deletion itself affects mitochondrial proteins in a minor way that may not cause disease, but in the 25 percent who have schizophrenia, there’s some kind of genetic second hit that’s affecting mitochondrial function enough to push them over a threshold to get sick.”

Dr. Anderson and colleagues are taking two separate approaches to identify whether mitochondrial function follows a pattern that matches this two-hit hypothesis.

The first approach to answering this question uses neurons grown in the lab from induced pluripotent stem cells using samples from individuals with 22q11.2DS with and without schizophrenia, and from healthy controls. By testing these lab-grown neurons for their mitochondrial functions, Dr. Anderson and colleagues hope to determine if the functional level of each group’s mitochondria matches the pattern of their hypothesis: Fully functional in the healthy controls, less functional in those with 22q11.2DS but without schizophrenia, and still even less functional in those with the deletion who do have schizophrenia. In their preliminary experiments to date, they have found evidence that neurons with 22q11.2DS have disrupted mitochondrial function compared to the healthy controls. The experiments comparing neurons from those with and without schizophrenia in combination with 22q11.2DS, and comparing those two groups with healthy controls, will begin this winter.

The second approach focuses on the genetics of mitochondrial function in samples from these three groups. Partnering with CHOP investigators Beverly Emanuel, PhD, a geneticist and professor of Pediatrics at the Perelman School of Medicine at Penn, and Larry Singh, PhD, a computational geneticist in CMEM, the team will use samples from the International 22q11.2 Brain Behavior Consortium, a collaborative international study on which Dr. Emanuel is a co-investigator. They will sequence genes in the mitochondria and in nuclear DNA that affect mitochondrial function to see if the sequences bear out the second-hit hypothesis as a mechanism for schizophrenia cases associated with this chromosomal deletion.

“We hope we can show that, if you have the 22q deletion, you’re more likely to have schizophrenia if you also have a mutation in any one of these thousand other mitochondria-functioning genes,” Dr. Anderson said. “If that’s the case, we can then build an assay to look at whether there is a pattern of mutation that’s predictive of the development of schizophrenia prospectively. We could also use such laboratory assays as drug discovery platforms to see what compounds seem to be effective at restoring mitochondrial function.”

Predicting the onset of schizophrenia in children before they develop symptoms could open up possibilities for prevention, a concept that Dr. Anderson noted is the core of the new Lifespan Brain Institute at CHOP and Penn, which is directed by Raquel Gur, MD, PhD, and encompasses broad collaborations between investigators at CHOP and Penn.

“We know that neuropsychiatric illnesses that present in later childhood, adolescence or adulthood, have pathological antecedents that start way before symptoms begin,” Dr. Anderson said. “Ideally, we’d really like to intercept the pathological process before people get sick, or before they get any sicker than necessary. The institute was designed in order to facilitate interactions between CHOP, where we’re more focused on the child end, and Penn, where they’re more focused on the adult end but including very young adults. Our goal is to learn what is the typical trajectory of brain development and brain function and, by studying children at high genetic risk for developing mental illnesses, how to best identify when that typical trajectory is being derailed. Then we can figure out new approaches for getting the process back on track.”

In addition to these goals to benefit patients with schizophrenia, Dr. Anderson hopes that the mitochondrial genetics portion of the project will provide added insights for individuals with 22q11.2DS about risks for other diseases. The team plans to share this genetic data as a public resource over the next few years, which could lead to future discoveries of mitochondrial genes’ roles in the risk for cardiac and movement disorders in this population.

More broadly, this project is just one of a growing number of efforts to look at the role of mitochondrial bioenergetics in the brain as a mechanism of neurological and psychiatric conditions. Dr. Wallace, a renowned leader and founder of the field of mitochondrial medicine, has long argued that a traditional biomedical approach focused on the organ exhibiting the most prominent symptoms of a disease (such as the brain) overlooks the key role played by systematic bioenergetics in health. Last year, he led a study published in the Proceedings of the National Academy of Sciences (PNAS) showing that small changes in mitochondrial genes had substantial impacts on physiological stress responses in a mouse model. Recently, he was awarded a new NIMH grant to study whether a major contributor to autism spectrum disorder could be the inhibition of interneurons and defects of developmental migration of interneurons caused by partial mitochondrial dysfunction.

“While human differences in behavior and its relation to predisposition to mental illness as well as to a wide variety of pediatric and adult neurological diseases has been the subject of intense investigations for over a century, we still have a rudimentary understanding of the physiological, genetic, and environmental factors that mediate mental health and illness,” Dr. Wallace said after the PNAS paper was published last year. “Our recent papers strongly suggest that by reorienting our investigations from the anatomy of the brain and brain-specific genes to the mitochondria and the bioenergetics genes, we may have a more productive conceptual framework to understand neuropsychiatric disease. If so, this will spawn a whole new generation of neuropsychiatric therapeutics.”

If your child had a serious and complex disease, one that affected multiple organs and systems — perhaps impairing her growth, her ability to move, her liver function, her vision, her heart, her brain, or a combination of several or all of these with progressive involvement occurring in other parts of the body — you would want an explanation of what went awry in her health and development. You would also want treatments to help restore her health, prevent further decline, improve her quality of life, or to extend her life if it were endangered by her condition.

This unthinkable scenario is unfortunately familiar to families who experience mitochondrial diseases, a type of inherited metabolic disorder caused by genetic changes affecting the organelles inside cells that produce energy. Scientists have made substantial advances in answering families’ need for explanations, uncovering numerous distinct genetic defects in the genes carried within mitochondria themselves and in the genes in the cell’s nucleus that are essential to mitochondrial functions. In total, mutations in about 300 genes are now recognized to cause mitochondrial diseases, with different flaws in different genes manifesting with varied patterns of symptoms affecting potentially any systems in the body.

But doctors do not yet have a good response to families’ wish for proven treatments. There are not yet any therapies for mitochondrial diseases demonstrated to work in randomized, controlled trials or approved by the Food and Drug Administration (FDA). Marni Falk, MD, director of the Mitochondrial Disease Clinical Center at Children’s Hospital of Philadelphia and an associate professor of Pediatrics in the division of Human Genetics at the Perelman School of Medicine at the University of Pennsylvania, is a central figure in national and international collaborative efforts to bring together parties involved in mitochondrial disease research, clinical care, advocacy, pharmaceutical development, funding, and regulation, to move toward getting evidence-based and approved therapies to patients.

“There’s now growing recognition that, even though there have been no FDA approved therapies yet, we’re going to get there, but we have to work together,” Dr. Falk said.

National and International Collaborations Converge on Key Questions

An article published in the November 2016 issue of Molecular Genetics and Metabolism and co-authored by Dr. Falk summarizes the current state of research and is an outgrowth of that collaborative spirit. The report stems from a December 2014 meeting hosted by the Office of Dietary Supplements at the National Institutes of Health (NIH) that focused on the need for better study of the safety and efficacy of nutritional interventions for mitochondrial disease. Unable to write a prescription for a proven therapy, doctors often suggest a stop at the health food store, guiding patients toward nutritional supplements such as vitamins and cofactors that are thought to help boost cellular energy metabolism. There are added challenges for evaluating these supplements as potential therapies, including the fact that the FDA regulates supplements less stringently than drugs.

Dr. Falk noted that even more significant progress on finding new treatments for mitochondrial disease, both nutritional and pharmaceutical ones, gained momentum after the NIH meeting. In October 2015, Dr. Falk organized a Critical Path Innovation Meeting (CPIM) hosted by the FDA that focused on a series of thought questions for open discussion — not about a specific drug or a specific therapy — but on the leading challenges mitochondrial experts collectively face, such as how to most efficiently, practically, and effectively get to therapy.

“Patients have on average 16 different symptoms, so which ones are we going to pick to target?” Dr. Falk asked. “Are we going to test therapies that exist in the health food store, and if so is our goal to obtain FDA approval? Are we going to test therapies that are brand-new ideas that a pharmaceutical company has come up with, regardless of pre-clinical evidence in mitochondrial disease models? What’s the standard of care? What’s the right way to design a trial in such a heterogeneous disease? There’s hundreds of different manifestations and causes, so how are we going to classify and treat patients? These diseases involve 300 different genes, with every potential organ being involved, so how are you going to know if the drug worked? That was the overall scope of the conversation.”

Dr. Falk also continues to contribute to larger international collaborations. Following the CPIM, she joined the program organizing committee of a new biannual meeting sponsored by the Wellcome Trust in the U.K. to convene researchers and pharma together for focused discussion of developing and testing therapies in mitochondrial disease. The Mitochondrial Disease Sequence Data Resource (MSeqDR) web portal she helped develop was recently adopted as the data use and sharing platform for a multi-national European consortium of mitochondrial disease researchers, Genomit.

Charting the Path from Basic Discovery to Clinical Trials

In Dr. Falk’s lab and other basic research labs, scientists are making substantive progress in describing how the cell’s molecular pathways are affected by changes in mitochondrial genes, and in testing compounds that improve functioning in cell and animal models. For instance, Dr. Falk recently received renewed NIH funding for studies of drug therapies in animal models of mitochondrial complex I disease. In the first phase of this work, her team found a series of drug candidates that were effective in improving the lifespan of worms, C. elegans, with mitochondrial defects equivalent to those in subsets of human disease.

In the new phase, they will test these drugs in various combinations and range of mitochondrial defects, as well as extend their work in collaboration with the recently established CHOP Zebrafish Core Facility into zebrafish, a vertebrate animal model with distinct organ systems. Dr. Falk’s lab is making similar progress in extending this pre-clinical translational research approach to create additional animal and human cell models of disease based on individual patients’ genetic mutations, in work funded with philanthropic support of family foundations, as well as with the support of research contracts from pharmaceutical companies to test the efficacy and toxicity of emerging therapeutic candidates across different forms of mitochondrial disease.

But the next stretch of the journey, taking promising drugs from animal models into clinical trials to evaluate whether they benefit human patients with mitochondrial disease, is more of a rocky unknown. Charting this path is why it was so important for national and international collaborators to exchange ideas with regulators.

Many of the challenges facing mitochondrial disease are similar to those involved in other rare diseases, such as pediatric cancers. Because there are few patients with these diseases at all, and even fewer with any given genetic subtype of disease, it is difficult or impossible to form large enough populations to conduct traditional clinical trials for precision therapies — even more so when clinical symptoms vary between individuals. The discussion at the CPIM laid groundwork for researchers to understand the types of trials the FDA could find useful in generating meaningful evidence with smaller subgroups of patients or with individualized outcome measures. The discussion also made it clear to researchers that it is essential to involve the FDA early in the process of planning these trials.

Knowledge about the natural history of mitochondrial diseases is also lacking, making it difficult to know whether or not changes in a patient’s symptoms over time are the result of a specific intervention. Efforts are now underway to collaboratively build up that knowledge of the natural history of mitochondrial diseases, including through the NIH-supported North American Mitochondrial Disease Consortium, of which CHOP is an active site.

The shortage of good outcome measures for mitochondrial diseases is also a roadblock to progress in clinical trials and clinical management of disease, but multiple efforts underway at CHOP and elsewhere are building better technologies, biomarkers, and surveys that can measure meaningful progress.

Closely involving the mitochondrial disease patient community is also essential in learning the aspects of disease that patients prioritize to participate in treatment trials. For example, a survey being prepared for publication that was conducted across both CHOP and national mitochondrial disease patient cohorts revealed fatigue and exercise intolerance to be the most common and prioritized treatment symptoms across all disease causes. A Family Advisory Council was also recently established to directly involve families in the growth and activities of the CHOP Mitochondrial Disease Clinical Center.

Building a ‘Critical Mass’ to Help Families at CHOP and Worldwide

At CHOP, Dr. Falk is building the groundwork for what she hopes will be new clinical trials for mitochondrial diseases in the next year or two. CHOP is already a site for a pharmaceutical company-sponsored trial for adults with mitochondrial myopathy. Active discussions are underway with additional pharmaceutical companies, patient advocacy organizations including the United Mitochondrial Disease Foundation, and families to shape and fund anticipated future efforts.

In the clinic, the national and global efforts manifest as a movement toward getting families what they most want and deserve — not just explanations, but also solutions. The Mitochondrial Disease Clinical Center is expanding, integrating care with more than a dozen specialists across CHOP who recognize and can treat various aspects of mitochondrial diseases. Dr. Falk envisions a near future when, just like a child who receives a diagnosis of cancer, a child diagnosed with mitochondrial disease will be offered a standard of care treatment plan and options for clinical trials of new therapies tailored to their subtype of disease.

“I think we’re getting enough critical mass to make CHOP poised to be very successful at coming up with better understanding of mitochondrial disease mechanisms, better understanding of lead treatment candidates, and then doing the transition right here from the preclinical ‘aha!’ moment to the clinical trial, and establishing new standards of care that we can then make available to our patients in the clinic,” Dr. Falk said. “Because it’s all being done right here, we hope it will be a shorter, collapsed cycle of discovery, to get to evidence-based treatments faster than ever before.”

A new word is catching on to describe the sometimes overwhelming life stage of learning to behave like a grown-up: “adulting.” For youth with chronic diseases, adulting has complexities beyond coming to grips with doing their own laundry. They must transition to a new system of adult-centered medical care, which can be daunting.

Several changes converge as adolescents age out of the pediatric health system. They may be graduating high school, moving out on their own, making their own medical and legal decisions independently, choosing insurance coverage, and encountering changing eligibilities and covered services for federal programs such as Medicaid. In the midst of this flux, it is not uncommon for young adults with chronic conditions to have lapses in medication, supplies, and physician visits.

“Most children with chronic diseases get very excellent care as children,” said Sophia Jan, MD, who is a pediatrician for children with special healthcare needs at Children’s Hospital of Philadelphia and a general internist at the University of Pennsylvania Health System. “They’re reaching their potential, meeting life milestones, and living into adulthood. But what typically happens when they turn 18 or 21 is that they fall off a cliff of medical and other services. Many young adults with chronic disease have a very difficult time during this transition from pediatric care to adult care.”

Dr. Jan, who also is an associate program director of the Combined Internal Medicine-Pediatrics Residency Program and a faculty member of CHOP’s PolicyLab, has seen too many patients teetering on this cliff. With the help of funding from the Health Resources & Services Administration, Dr. Jan along with co-principal investigators David Rubin, MD, MSCE, PolicyLab director, and Lawrence Brown, MD, a CHOP pediatric neurologist, will lead a quality improvement study team to implement a bundle of programs and interventions to safely transition this vulnerable population, focusing on those with epilepsy, to adult care. The transition interventions are based on a set of guidelines that Dr. Brown developed along with a panel of experts convened by the Child Neurology Foundation that serve as a blueprint to help clinicians transition children with a variety of neurologic conditions, taking into account that they also may concurrently have intellectual disabilities that affect their decision-making.

“We’re seeing how we can implement these guidelines in real-world settings,” Dr. Jan said. “This project is probably one of the largest implementations of transition-related interventions at a large free-standing children’s hospital and a separate large adult medical center.”

They will partner with the University of Pennsylvania Health System to build a learning collaborative with seven clinical sites (two CHOP pediatric neurology practices, two CHOP primary care practices, two Penn adult neurology practices, and a Penn adult neurology practice) that will collect data to assess the ongoing effectiveness of the interventions. The project, Improving Access to Care and Transition Services for Children and Youth With Epilepsy in Eastern Pennsylvania (I-ACT for Epilepsy), is expected to reach 1,000 children and youth living with epilepsy in the catchment areas of CHOP and the University of Pennsylvania Health System.

The study aims to help patients like a young woman with epilepsy and cerebral palsy who Dr. Jan met for the first time, without having any background on her previous medical history. She was nonverbal, used a feeding tube, and was dependent on her grandmother for all aspects of her daily living. In order to be seen in Dr. Jan’s adult practice at Penn, the young woman needed to change insurance, and her family was scrambling to get new medical suppliers and nursing care services in place. Most worrisome, at the time, was that she didn’t have a clear plan on how she was going to continue receiving her regular botox injections to treat her spasticity. Dr. Jan acted immediately to redo all of her prior authorizations and letters of medical necessity to avoid any lapses in services or medications that could lead to a potentially dangerous situation for her new patient.

Ideally, the components of I-ACT for Epilepsy will smooth out some of those issues. The study team is working to create a registry of patients with epilepsy so that they can better track their access to care and quality measures around transitions of care. They are building the infrastructure to integrate that information into the electronic medical records at CHOP and Penn.

A full suite of clinician decision support tools also will be available to facilitate transition best practices and discussions about shifting care from pediatric to adult providers. For example, an alert will prompt pediatric providers to select patient/family education sheets about transition topics. Checking another box will recommend a consult with a social worker.

“It’s a way to break all the parts of transition into small chunks to make it more feasible and less overwhelming from the standpoint of providers,” Dr. Jan said. “Instead of being crisis driven, let’s proactively think about what issues a patient who is 16 or 17 is going to face in the next 12 months in order to safely transition their care to adult providers in a different system.”

Another part of the intervention bundle is assessing patients’ transition readiness so that the study team can pinpoint which basic competencies patients might need the most help with. Do they know what medications they take and how often? Do they know who to call in an emergency? Do they know how to set up a medical appointment? A youth community health worker who has epilepsy will be recruited from one of the adult care practices participating in the study to work with a select group of patients to help them develop these specific efficacy skills and troubleshoot navigating the adult healthcare system.

The study team also is working to standardize a transition summary document that will inform adult care physicians in advance about a complex patient’s most important active medical issues so that they can accommodate the extra time and attention that they’ll need when they assume their care. They will implement new clinical pathways, some that may be shared between CHOP and Penn, to streamline some of the communication barriers that historically happen between pediatric and adult hospitals.

Several of these strategies already have been pilot tested by CHOP’s Multidisciplinary Intervention Navigation Team (MINT) for Pediatric to Adult Medical System Transitions that Dr. Jan coordinates along with attending physician Dava Szalda, MD; nurse practitioner Adam Greenberg; social workers Symme Trachtenberg and Caren Steinway; and youth community health worker Katie Wu. MINT is deployed to help transition CHOP’s most complex patients to Penn. It is a project funded by the Department of Pediatrics’ Chair’s Initiative at CHOP, which is a program that provides funding to support special projects to establish new models of care in pediatrics.

Even with some of the groundwork done, I-ACT is an ambitious project. Among its goals is to increase by 50 percent the number of children and youth with epilepsy served by the clinical sites who have a youth transition plan in place. While I-ACT focuses on epilepsy, Dr. Jan points out that the lessons they learn will be applicable across programs who help young adults with other chronic diseases transition to adult services.

“If we can show that we can improve transitions of care between two large hospital systems with these particular tools and use metrics that are measurable through their electronic medical records, then we will have both a clinical process and suite of tool sets that will be a good model for other institutions to potentially use to improve transitions of care,” Dr. Jan said.